The object is to discover and account for the minimal essential changes in enzyme pattern that are necessary to convert to a parenchymal liver cell or its immediate precursor into a hepatocellular carcinoma, working in terms of the hypothesis that "oncogeny is blocked ontogeny". The method is to study the enzyme pattern and its alteration under hormonal or dietary stimulation in fetal, neonatal, regenerating and adult liver in comparison with transplantable and primary hepatomas in whole animals and in cell cultures. The hypothesis implies that an altered capability for normal differentiation can result in a permanent maintenance of fetal enzymes necessary for cell division and an inclusion of nearly all intermediate stages of differentiation in one hepatoma line or another. With the above-mentioned liver systems or hepatomas for standards, our main emphasis will be on primary cultures of isolated single liver cells maintained as sterile monolayers for up to one week or more. In these cultures enzyme induction can be studied to determine the factors affecting the availability and functioning of the genome in normal and transformed cells. The enzymes to be emphasized will be in several categories. One class will be those connected with DNA synthesis, such as thymidine kinase, thymidylate synthetase, DNA polymerase(s), and ribotide reductase. A second class will be those enzymes that represent "whole organism-oriented functions" (WOOF enzymes). These enzymes will be found in adult liver and frequently not at all in fetal liver. Glucokinase is an example. A third class will be glycolytic isozymes that exist in fetal and adult forms. Pyruvate kinase is an example. A fourth class will be enzymes that have very short half-lives, such as ornithine decarboxylase.